Project Summary Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence of circulating autoantibodies to nucleic acids and to proteins with which they associate. Signaling through the nucleic acid sensing TLR, TLR7 and TLR9, is critical in SLE pathogenesis, and dysregulated TLR signaling can promote lupus in humans and in mouse models. Plasmacytoid dendritic cells (pDC) and B cells both express these nucleic acid sensing TLR and are important in SLE pathogenesis. Autoreactive B cells produce pathogenic autoantibodies in SLE, and B cell antibody production is promoted by TLR7 and TLR9 signaling. pDC use TLR7 and TLR9 to respond to nucleic acids in immune complexes resulting in the secretion of large quantities of type I IFN cytokines, which have pleiotropic effects on the immune response, including enhancing dendritic cell (DC) maturation, plasma cell formation, and T cell responses, all of which can promote a feed forward loop of immune activation. Therefore, understanding the mechanisms by which TLR7 and TLR9 signaling are regulated in these two critical cell types is important for understanding the pathogenesis of SLE and in defining therapeutic targets for this disease. We have made the novel discovery that the signaling adapter BCAP is highly expressed in pDC and is required for type I IFN production in response to TLR7 and TLR9 agonists from these cells. We also show for the first time that BCAP has a role in B cell TLR7 and TLR9 responses, and that loss of BCAP ameliorates disease development in a mouse model of lupus. Thus, BCAP is a key regulator of TLR7 and TLR9 function in pDC and B cells, and understanding how BCAP regulates TLR7/9 signaling in these cells will help identify new therapeutic targets in lupus and other IFN-associated autoimmune diseases. In aim 1, we will determine how BCAP regulates TLR7/9 responses in pDC and B cells, with a focus on mechanistic work and translation. In aim 2, we will determine the relative contribution of BCAP in pDC and B cells to the development of SLE using 2 mouse models, TLR7.1 mice and B6.Sle1.Yaa mice. Understanding the role of BCAP in pDC and B cell TLR7/9 responses will give us insights into lupus pathogenesis and allow us to evaluate BCAP as a therapeutic target in SLE.